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Parkinsonism in GNDs392Early infantile epileptic encephalopathy 4 (STXBP1)Pathogenic variants in STXBP1 may cause significant impairment of complex I of the mitochondrial respiratory chain and may disrupt the selfreplicating aggregation of α-synuclein.26Glutaric aciduria type I (GCDH)GCDH plays a key role in the catabolism of lysine, hydroxylysine, and tryptophane. Deficiency of GCDH leads to accumulation of glutaric acid and 3-hydroxyglutaric acid that can induce neuronal death through excitotoxicity as well as mitochondrial dysfunction and altered neurotransmission.27Mevalonic aciduria (MVK) Pathogenic variants in MVK may result in mitochondrial dysfunction, impaired cholesterol biosynthesis, toxic basal ganglia mevalonate accumulation and intracerebral inflammation.28,29NR4A2 Pathogenic variants in NR4A2 are implicated in development and survival of dopaminergic neurons in the substantia nigra, and may lower expression of genes associated with mitochondrial function and oxidative phosphorylation.30Pyruvate carboxylase deficiency (PC)PC encodes for pyruvate carboxylase, a mitochondrial enzyme that catalyzes pyruvate to oxaloacetate, intermediates in the Krebbs cycle and is important for neurotransmitter synthesis.31SPG10 (KIF5A) Axonal transport defect of mitochondria has been shown in a KIF5Aknockout mouse model.32Autophagic-lysosomal systemAlexander disease (GFAP)GFAP encodes for glial fibrillary acidic protein (GFAP), an intermediate filament protein in astrocytes. GFAP accumulation has been associated with autophagy in astrocytic cells.33BPAN (WDR45) Pathogenic variants of WDR45, encoding for WIPI4 protein, may cause iron accumulation in the basal ganglia by impeding autophagy,34 that may result in neuroinflammation and swelling of the substantia nigra.Christianson syndrome (SLC9A6)SLC9A6 encodes the endosomal Na+/H+ exchanger 6 and is involved in endosomal luminal pH and trafficking, synapse development and plasticity.35 Findings in Slc9a6 knock-out mice were consistent with endosomal-lysosomal dysfunction.36DOORS syndrome(ATP6V1B2)ATP6V1B2 encodes a subunit of the lysosomal transmembrane proton pump. Altered lysosomal pH is associated with chronic changes in autophagy.37JNCL (CLN3) CLN3 is involved in autophagic-lysosomal function. CLN3 is required for fusion of autophagosomes to lysosomes.38Mucolipidosis type II (GNPTAB)Pathogenic variants in GNPTAB, that encodes for GlcNAc-1-phosphotransferase, may cause lysosomal accumulation of nondegraded material, leading to neuronal dysfunction.39NUS1 Deficiency of NUS1, encoding the Nogo B receptor, may result in lysosomal defects, most likely caused by lysosomal cholesterol accumulation.40RAB39B Ras-related proteins play an essential role in neuronal maintenance, survival and synapse formation. It has been suggested that RAB39B plays a role in autophagy of dopaminergic neurons. Loss of function may impair the clearance of α-synuclein.41, 42SPG15 (ZFYVE26) Pathogenic variants of ZFYVE26 encoding spastizin, a protein mediating autophagic lysosome reformation, are believed to cause abnormal lysosomal storage.43